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Rare mutations in IRF6 and GRHL3 cause Van der Woude syndrome, an autosomal dominant orofacial clefting disorder. Common variants in IRF6 and GRHL3 also contribute risk for isolated orofacial clefting. Similarly, variants within genes that encode receptor tyrosine kinase (RTK) signaling components, including members of the FGF pathway, EPHA3 and SPRY2, also contribute risk for isolated orofacial clefting. In the mouse, loss of Irf6 or perturbation of Fgf signaling leads to abnormal oral epithelial adhesions and cleft palate. Oral adhesions can result from a disruption of periderm formation. Here, we find that IRF6 and SPRY4 signaling interact in periderm function. We crossed Irf6 heterozygous ( Irf6+/-) mice with transgenic mice that express Spry4 in the basal epithelial layer ( TgKRT14::Spry4). While embryos with either of these mutations can have abnormal oral adhesions, using a new quantitative assay, we observed a nonadditive effect of abnormal oral epithelial adhesions in the most severely affected double mutant embryos ( Irf6+/-;TgKRT14::Spry4). At the molecular level, the sites of abnormal oral adhesions maintained periderm-like cells that express keratin 6, but we observed abnormal expression of GRHL3. Together, these data suggest that Irf6 and RTK signaling interact in regulating periderm differentiation and function, as well as provide a rationale to screen for epistatic interactions between variants in IRF6 and RTK signaling pathway genes in human orofacial clefting populations. [ABSTRACT FROM AUTHOR]

We launched a new intervention study called REPRINTS in which senior volunteers engaged in reading picture books to children. Sixty-nine volunteers and 72 participants in a control group, all aged 60 years and over, living in three urban locations, participated in a baseline health checkup in June 2004. After completion of a three-month training seminar, volunteers visited public elementary schools and kindergartens in groups of 6 to 10 for an 18 month period. They were assessed again by a follow-up health checkup in March 2006. At the follow-up, social network scores (frequency of contact with grandchildren and others around the neighborhood) and self-rated health improved or was maintained at a significantly higher rate for the 37 individuals volunteering most intensively as compared to those who did not volunteer or volunteered minimally. In conclusion, through intensively being engaged in the intergenerational volunteer programs during 21 months, self-rated health and social networks were more likely to improve or be maintained among senior volunteers than controls. [ABSTRACT FROM AUTHOR]

Abstract Background Induction of potent long lasting effector T cell responses against liver stage malaria antigens strongly correlates with protection from malaria. While Adenovirus serotype 5 (Ad5) based malaria vaccine platforms have the ability to induce potent effector T cell responses against transgenes, high rates of pre-existing Ad5 immunity in malaria endemic regions has prompted study of alternative Ad serotype based malaria vaccines as replacements for Ad5 based malaria vaccines. The research described in this article examines the utility of alternative serotype adenovirus serotype 4 (Ad4) expressing a sporozoite surface protein (circumsporozoite protein (CSP)) (Ad4-CSP) to induce immune responses against CSP. The immunogenicity of Ad4-CSP was also tested in homologous and heterologous prime boost vaccinations in both Ad5 naïve and Ad5 immune backgrounds as compared to use of Ad5-CSP. Results In Ad5 naïve animals, use of Ad4-CSP priming vaccinations followed by boosting with Ad5-CSP (Ad4-CSP/Ad5-CSP) maximally increased the numbers of CSP specific cytokine secreting cytotoxic T cells relative to repeated use of Ad5-CSP. The Ad4-CSP/Ad5-CSP regimen also induced equivalent levels of CSP specific cell killing as did homologous prime-boost vaccinations with Ad5-CSP, despite stimulating lower numbers of CSP specific cytotoxic T cells. Priming with Ad4-CSP followed by a homologous boost resulted in significantly less CSP specific humoral responses than any other vaccination regimen tested in Ad naïve animals. In Ad5 immune animals, addition of Ad4-CSP in homologous or heterologous prime boost resulted in inductions of higher CSP specific responses than animals repeatedly vaccinated with Ad5-CSP alone. However, the observed responses were well below those observed in similarly treated Ad naïve mice. Conclusions While the Ad4-CSP/Ad5-CSP and Ad5-CSP/Ad5-CSP vaccination regimens resulted in equivalent CSP specific killing in Ad naïve animals, Ad4-CSP/Ad5-CSP achieved this result with a lower percentage of CSP specific CD8+ T cells and a higher number of IFNγ secreting cells, suggesting that the Ad4-CSP/Ad5-CSP vaccination regimen elicits more efficient cytotoxic T cells. In Ad5 immune animals use of Ad4-CSP improved CSP specific immune responses as compared to repeated use of Ad5-CSP, but could not achieve the levels of immunogenicity observed when the same vaccine regimens were used in Ad naïve animals. These data indicate the existence of some level of immunological cross-reactivity between these two adenovirus subgroups. Based on these results, it is suggested that future studies should undertake similarly stringent analyses of alternative Ad serotypes to establish their effectiveness as replacements for Ad5.

Background: This case series describes the technical considerations and effectiveness of 'endovascular embolic hemispherectomy' for the treatment of medically intractable seizures in neonates and young infants with hemimegalencephaly (HME) and in whom surgical hemispherectomy is not a viable option., Methods: This is a descriptive review of the endovascular technique used to treat consecutive pediatric patients with serial transarterial embolization for intractable seizures due to HME between 2018 and 2022. Clinical presentation, endovascular procedural details and complications, and efficacy were examined., Results: Three infants (13-day-old, 13-week-old and 15-day-old) with HME and intractable seizures underwent a total of 10 transarterial embolizations. Anticipated intraprocedural events included vasospasm and focal subarachnoid hemorrhage in all three infants, effectively controlled endovascularly, and non-target embolization in one infant. No infants had symptomatic intracranial hemorrhage or femoral artery occlusion. EEG background quiescence and seizure cessation was achieved after the final stage of embolization in all patients. All infants were discharged home from the neonatal ICU (median length of stay 36 days, range 27-74 days) and remain seizure-free to date (4 years, 9 months, and 8 months). None have developed hydrocephalus, required surgical hemispherectomy or other neurosurgical interventions., Conclusion: Endovascular hemispherectomy can be safely used to provide definitive treatment of HME-related epilepsy in neonates and young infants when intraprocedural events are managed effectively. This less invasive novel approach should be considered a feasible early alternative to surgical hemispherectomy. Further studies are needed to enhance the safety profile and to assess long-term neurodevelopmental outcome and durability of freedom from seizures., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Inborn errors of metabolism are a diverse group of genetic disorders including many that cause neonatal-onset epilepsy such as pyridoxine-dependent epilepsy (PDE). PDE occurs secondary to biallelic pathogenic variants in ALDH7A1 and can present with refractory neonatal seizures and status epilepticus. Neonatal seizures and encephalopathy are modifiable with pyridoxine (vitamin B6) supplementation. However, the clinical response to pyridoxine supplementation can be delayed. We present the case of a full-term neonate with PDE in which seizure cessation was seen a few hours after intravenous pyridoxine load, but the improvement in EEG background and level of clinical encephalopathy occurred 5 days later. We share this case to provide an example in which clinical improvement in PDE was gradual and required continuation of treatment for several days illustrating the necessity of continuing vitamin B6 supplementation in suspected cases until confirmatory genetic testing is obtained or an alternate cause is found., (© 2023 American Academy of Neurology.)

Prenatal Zika virus (ZIKV) infection is a serious global concern as it can lead to brain injury and many serious birth defects, collectively known as congenital Zika syndrome. Brain injury likely results from viral mediated toxicity in neural progenitor cells. Additionally, postnatal ZIKV infections have been linked to neurological complications, yet the mechanisms driving these manifestations are not well understood. Existing data suggest that the ZIKV envelope protein can persist in the central nervous system for extended periods of time, but it is unknown if this protein can independently contribute to neuronal toxicity. Here we find that the ZIKV envelope protein is neurotoxic, leading to overexpression of poly adenosine diphosphate -ribose polymerase 1, which can induce parthanatos. Together, these data suggest that neuronal toxicity resulting from the envelope protein may contribute to the pathogenesis of post-natal ZIKV-related neurologic complications., Competing Interests: Declaration of Competing Interest The authors have no competing financial interests or other competing interests., (Published by Elsevier Inc.)

Background: Computational phenotypes are most often combinations of patient billing codes that are highly predictive of disease using electronic health records (EHR). In the case of rare diseases that can only be diagnosed by genetic testing, computational phenotypes identify patient cohorts for genetic testing and possible diagnosis. This article details the validation of a computational phenotype for PTEN hamartoma tumor syndrome (PHTS) against the EHR of patients at three collaborating clinical research centers: Boston Children's Hospital, Children's National Hospital, and the University of Washington., Methods: A combination of billing codes from the International Classification of Diseases versions 9 and 10 (ICD-9 and ICD-10) for diagnostic criteria postulated by a research team at Cleveland Clinic was used to identify patient cohorts for genetic testing from the clinical data warehouses at the three research centers. Subsequently, the EHR-including billing codes, clinical notes, and genetic reports-of these patients were reviewed by clinical experts to identify patients with PHTS., Results: The PTEN genetic testing yield of the computational phenotype, the number of patients who needed to be genetically tested for incidence of pathogenic PTEN gene variants, ranged from 82 to 94% at the three centers., Conclusions: Computational phenotypes have the potential to enable the timely and accurate diagnosis of rare genetic diseases such as PHTS by identifying patient cohorts for genetic sequencing and testing., (© 2022. The Author(s).)

Background: Congenital Zika infection can result in a spectrum of neurological abnormalities in the newborn. Newborns exposed to Zika virus in utero often have neuroimaging as part of their clinical evaluation., Methods: Through the Congenital Zika Program at Children's National Health System in Washington DC, we performed fetal or neonatal neuroimaging, including magnetic resonance imaging and ultrasound, on over 70 fetuses or neonates with intrauterine Zika exposure. Novel findings on neonatal brain magnetic resonance imaging were observed in two instances., Results: Gadolinium-contrast magnetic resonance imaging showed enhancement of multiple cranial nerves at three days of age on one infant. Another infant underwent magnetic resonance imaging at 16 days of age and was shown to have a chronic ischemic cerebral infarction. This infant had previously normal fetal magnetic resonance imaging., Conclusion: Cranial nerve enhancement and cerebral infarction may be among the expanding list of neurological findings in congenital Zika infection. Postnatal brain magnetic resonance imaging should be considered for newborns exposed to Zika virus in utero., (Copyright © 2017 Elsevier Inc. All rights reserved.)

We have developed a soft x-ray time-resolved photoemission spectroscopy system using synchrotron radiation (SR) at SPring-8 BL07LSU and an ultrashort pulse laser system. Two-dimensional angle-resolved measurements were performed with a time-of-flight-type analyzer. The photoemission spectroscopy system is synchronized to light pulses of SR and laser using a time control unit. The performance of the instrument is demonstrated by mapping the band structure of a Si(111) crystal over the surface Brillouin zones and observing relaxation of the surface photo-voltage effect using the pump (laser) and probe (SR) method.

An ionic liquid having a hydroxyl group, choline bis(trifluoromethylsulfonyl)amide ([N(111(2OH))][N(Tf)(2)]), was synthesized to investigate the effect of hydroxyl groups on the proton transport. 1,1,1-Trifluoro-N-(trifluoromethylsulfonyl)methanesulfoneamide (HN(Tf)(2)) as a proton source was mixed with the choline derivative at various molar ratios. Their thermal properties, viscosities, and ionic conductivities were investigated. [N(111(2OH))][N(Tf)(2)] showed a melting point at 27 °C, and its thermal stability was higher than 400 °C. The viscosity of [N(111(2OH))][N(Tf)(2)]/HN(Tf)(2) mixtures increased as the acid molar fraction increased. The ionic conductivity of [N(111(2OH))][N(Tf)(2)] was 2.1 × 10(-3) S cm(-1) at 25 °C; the ionic conductivity monotonously decreased as the acid molar fraction increased. There was a clear correlation between the ionic conductivity and the viscosity for the mixtures of the choline derivative and the acid. PFG-NMR measurements were carried out to investigate the diffusion behavior of protons. Although the acid and the hydroxyl group were indistinguishable by (1)H NMR, the self-diffusion coefficient of the (1)H of the hydroxyl group and the acid was larger than those of other (1)H nuclei. This difference suggests that a fast intermolecular proton transfer exists between the hydroxyl group and the acid., (This journal is © the Owner Societies 2011)

Background: Malaria greatly impacts the health and wellbeing of over half of the world's population. Promising malaria vaccine candidates have attempted to induce adaptive immune responses to Circumsporozoite (CS) protein. Despite the inclusion of potent adjuvants, these vaccines have limited protective efficacy. Conventional recombinant adenovirus (rAd) based vaccines expressing CS protein can induce CS protein specific immune responses, but these are essentially equivalent to those generated after use of the CS protein subunit based vaccines. In this study we combined the use of rAds expressing CS protein along with rAds expressing novel innate immune response modulating proteins in an attempt to significantly improve the induction of CS protein specific cell mediated immune (CMI) responses., Methods and Findings: BALB/cJ mice were co-vaccinated with a rAd vectors expressing CS protein simultaneous with a rAd expressing either TLR agonist (rEA) or SLAM receptors adaptor protein (EAT-2). Paradoxically, expression of the TLR agonist uncovered a potent immunosuppressive activity inherent to the combined expression of the CS protein and rEA. Fortunately, use of the rAd vaccine expressing EAT-2 circumvented CS protein's suppressive activity, and generated a fivefold increase in the number of CS protein responsive, IFNγ secreting splenocytes, as well as increased the breadth of T cells responsive to peptides present in the CS protein. These improvements were positively correlated with the induction of a fourfold improvement in CS protein specific CTL functional activity in vivo., Conclusion: Our results emphasize the need for caution when incorporating CS protein into malaria vaccine platforms expressing or containing other immunostimulatory compounds, as the immunological outcomes may be unanticipated and/or counter-productive. However, expressing the SLAM receptors derived signaling adaptor EAT-2 at the same time of vaccination with CS protein can overcome these concerns, as well as significantly improve the induction of malaria antigen specific adaptive immune responses in vivo.

Background and Purpose: We have launched a new intervention study, called "REPRINTS" (Research of productivity by intergenerational sympathy), in which senior volunteers aged 60 years and over are engaged in reading picture books to school children, regularly visiting public elementary schools since 2004., Methods: So far, no repeated cross-sectional studies to demonstrate indirect effects on parents have been reported, although reciprocal effects on senior volunteers and children have been demonstrated. The purpose of this study was to examine the changes of evaluation of "REPRINTS" program by parents of school children during the 2 years., Subjects & Setting: Four to six volunteers as a group visited an elementary school in a suburb of Kawasaki city twice a week to read picture books. A baseline survey was conducted one month after launching the volunteer activity. First to fourth follow-up surveys were conducted every 6 months after baseline surver. Of 368 parents, 230 whose children were in 1st-4th grade were analyzed., Measurements: School grade of children, gender, emotional image scale of older adults by the SD (Semantic Differential) method (13 items), parents' evaluation of activity of "REPRINTS" volunteers such as promotion of reading for children, or children's respect for older adults, appreciation, familiarity with older adults, indirect effects on promotion of safety in the community, and reducing parent's physical and psychological burdens of volunteer service for school. Repeated cross-sectional analyses by ANCOVA, adjusted for confounding factors, were conducted in order to compare changes in responses between parents of 1st-2nd grade children (lower-grade children) with those of 3rd-4th grade-children (middle-grade children). We examined experiences of being read with picture books, greeting and having conversations with volunteers among all of 330 students of 1st-4th grade. These three items were examined using Chi-squared test to compare longitudinal change between parents of lower-grade and middle-grade children., Results: Evaluation of children's familiarity with older adults significantly declined among parents of middle-grade children, but was maintained among those of lower-grade children during the 2 years. Physical burdens of volunteer service for school were lower among parents' of lower-grade children at baseline, and were significantly reduced among parents' of all grades. Promotion of reading for children, indirect effects on promotion of safety in the community, and frequency of hearing episodes of "REPRINTS" volunteers from children were higher among parents' of lower-grade children at baseline. Psychological burdens were reduced and level of knowledge of "REPRINTS" volunteers was increased among parents' of all grades. In terms of parents' emotional image scale of older adults in general, no significant difference was found among the grades of school children and number of surveys for all the subscales of 'socialization', 'activity', and 'cheerfulness'., Conclusion: The level of knowledge and a number of items of evaluation of "REPRINTS" volunteers were significantly increased among parents of both lower-grade and middle-grade children during the 2-year intervention. This study indicates that the "REPRINTS" program can contribute to establishing trust and reliance between generations of older adults and parents of school children with the children as mediators.

Purpose: This study was conducted to examine the effect of increased physical and/or intellectual activities on changes in cognitive function in elderly dwellers., Methods: The subjects comprised 61 residents aged 65 or over living in Suginami Ward, Tokyo, who took part in a community-based dementia prevention class aimed at increasing both physical and intellectual activities. Physical activity was evaluated by the number of daily steps using a pedometer. Intellectual activity was evaluated by the number of pictures taken by a cellular phone and/or submitted through an internet "Dress" system by cellular phone. These activities were classified into two groups (higher and lower activity groups) according to whether above or below the respective median value. For assessment, the subjects underwent tests of physical and cognitive functions before and after the 7-weeks intervention., Results: Subjects with a greater increment in physical activity during the intervention period showed a greater improvement in usual and maximal walking speed than did those with a lesser increment in physical activity. Analysis using the general linear model demonstrated that increase in physical activity independently correlated with improvement in physical function, but did not correlate with cognitive function. Subjects with a greater increment in intellectual activity showed a greater improvement in weight, BMI and trail making test-task B. This association was independent of potential confounders. Further, those who used the "Dress" system more often showed a greater improvement in stress coping tests. Analysis using a general linear model indicated that increased intellectual activity was independently associated with changes in cognitive and mental function., Conclusion: The present findings suggest that community-based dementia prevention classes should be stressed not only for increasing physical activity but also in order to stimulate intellectual activity.

Background and Purpose: We have launched a new intervention study, called "REPRINTS" (Research of productivity by intergenerational sympathy) in which senior volunteers aged 60 years and over engage in reading picture books to school children, regularly visiting public elementary schools since 2004. The purpose of this study was to clarify characteristics of images of older people held by elementary school children and factors associated with such images, as well as to examine changes in images through intervention by "REPRINTS" senior volunteers (volunteers) for the initial one year period., Subjects & Setting: Four to six volunteers as a group visited A elementary school in a suburb Kawasaki city (470 students) twice a week to read picture books. The baseline survey was conducted one month after launching the volunteer activity. First and second follow-up surveys were conducted at 6 month intervals after the baseline survey., Measurements: Grade, gender, short version of emotional-like image scale of older adults assessed by the SD (Semantic Differential) method (6 items in the subscale for "evaluation" and 4 items in the subscale for "potency/activity"), experience of living with grandparents, experience of interchange with older people, frequency of interchange with volunteers and the social desirability scale for children., Result: Related variables for a higher score in the subscale for "evaluation" included lower grade and abundant experience of interchange with older people such as grandparents. Those for "potency/ activity" included lower grade, male gender, and a higher social desirability scale for children in the multiple logistic regression model. Students were divided into two groups in terms of frequency of interchange with volunteers (low and high-frequency groups) through three surveys. In the subscale for "evaluation", the general linear model demonstrated a significant interaction between the group and number of surveys adjusted for confounding factors., Conclusion: Although emotional images of older people significantly decline with advancing grade, those of students with a high frequency of interchange with volunteers were here found to be maintained more positively over one year compared to those with a low frequency.